title: Diversity through phosphine catalysis identifies octahydro-1,6-naphthyridin-4-ones as activators of endothelium-driven immunity.
abstract: The endothelium plays a critical role in promoting inflammation in cardiovascular disease and other chronic inflammatory conditions, and many small-molecule screens have sought to identify agents that prevent endothelial cell activation. Conversely, an augmented immune response can be protective against microbial pathogens and in cancer immunotherapy. Yet, small-molecule screens to identify agents that induce endothelial cell activation have not been reported. In this regard, a bioassay was developed that identifies activated endothelium by its capacity to trigger macrophage inflammatory protein 1 beta from primary monocytes. Subsequently, a 642-compound library of 39 distinctive scaffolds generated by a diversity-oriented synthesis based on the nucleophilic phosphine catalysis was screened for small molecules that activated the endothelium. Among the active compounds identified, the major classes were synthesized through the sequence of phosphine-catalyzed annulation, Tebbe reaction, Diels-Alder reaction, and in some cases, hydrolysis. Ninety-six analogs of one particular class of compounds, octahydro-1,6-naphthyridin-4-ones, were efficiently prepared by a solid-phase split-and-pool technique and by solution phase analog synthesis. Structure-function analysis combined with transcriptional profiling of active and inactive octahydro-1,6-naphthyridin-4-one analogs identified inflammatory gene networks induced exclusively by the active compound. The identification of a family of chemical probes that augment innate immunity through endothelial cell activation provides a framework for understanding gene networks involved in endothelial inflammation as well as the development of novel endothelium-driven immunotherapeutic agents.
authors.affiliation: Department of Medicine, Division of Cardiology, A2-237 Center for Health Sciences, University of California, Los Angeles, CA 90095-1679, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Cruz
authors.forename: Zhiming
authors.initials: Z
authors.lastname: Wang
authors.forename: Jon
authors.initials: J
authors.lastname: Kibbie
authors.forename: Robert
authors.initials: R
authors.lastname: Modlin
authors.forename: Ohyun
authors.initials: O
authors.lastname: Kwon
mesh_terms: D002384:Catalysis; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000276:immunology* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000276:immunology; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007155:Immunologic Factors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D015394:Molecular Structure; D010720:Phosphines / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D006571:Heterocyclic Compounds; D007155:Immunologic Factors; D010720:Phosphines; C044646:phosphine